The efficacy of many therapeutic and diagnostic agents is predicated on the ability of these agents to be retained within the vascular compartment or to be carried within the vascular compartment to their target within a mammal. Unfortunately, many of these agents when they are within the vascular compartment appear particulate in size, as this concept is defined below in Section 4.1. Because these agents activate or prime phagocytes (phagocytic cells) that are present within the vascular compartment and in fixed tissues of the body, they are susceptible to phagocytosis and pinocytosis. The triggering of these two processes in turn results in the accelerated removal of these agents from the vascular compartment. These agents are then stored within the organs of the reticuloendothelial system, as well as other tissues, until they are metabolized or excreted. In this context, the length of time during which these agents are within the vascular compartment, that is, their vascular dwell-time (intravascular persistence), is relatively short. Because these agents display short dwell-times within the vascular compartment, the ability of these agents to express their efficacy is severely compromised.
Furthermore, when the phagocytic response induced by these agents is particularly pronounced, the phagocytes that are present within the vasuclar compartment and the fixed tissues of the body often trigger a number of secondary responses which, in turn, cause a number of negative side-effects. For example, activation of phagocytes is known to cause the release of cytokines, such as Tumor Necrosis Factor (TNF) and Interleukin I, as well as ecoisanoids, such as Thromboxane A.sub.2 and Prostaglandin E.sub.2.
These cytokines and ecoisanoids can cause fever, back pain and pulmonary hypertension. See Inflammation: Basic Principles and Clinical Correlates (J. I. Gallin, I. M. Goldstein and R. Snyderman eds. 1988). Similarly, it has been observed that mammals that have received a particulate fluorocarbon suffer from cachexia. Cachexia is the name given to a generally weakened condition of the body or mind resulting from any debilitating chronic disease. Typical symptoms of cachexia include severe weight loss, depression, loss of appetite, anorexia and anemia. Cachexia is normally associated with neoplastic diseases, chronic infectious diseases or thyroiditis, and is a particular problem when associated with cancerous conditions. In particular, cachexia often compromises a mammal's response to chemotherapy and radiotherapy. This condition, in particular, is believed to be induced by the secretion of the cytokine TNF. See Tracey, K. J. et al. "Cachectin/Tumor Necrosis Factor Induces Cachexia, Anemia, Inflammation," J. Exp. Med 167:1211-1227 (1988).
Traditionally, the obstacles posed by increased phagocytic activity have been overcome by the sophisticated regulation of a number of parameters, including the regulation of the size of these agents, the dosage employed, the rate of infusion and the frequency with which these agents are administered.
In this context, there is need within the art to extend the vascular dwell-time of these agents and, therefore, counter the effects of phagocytosis, by methods that are not predicated on the intricate regulation of the aforementioned parameters.